PROJECT SUMMARY Heart failure following myocardial infarction (MI) is a leading cause of morbidity and mortality in the United States. MI involves cardiomyocyte death, inflammation, and remodeling of the left ventricle, which results in the formation of scar tissue and long-term loss of heart function. One therapeutic strategy is to selectively replace lost cardiomyocytes; however, there are significant challenges to identifying a cell source and engrafting viable cardiomyocytes in the injured myocardium. An alternative is to induce the proliferation of remaining cardiomyocytes towards the regeneration of functional myocardium. Our collaborators in the Morrisey group recently showed that daily, systemic injections of miR302 mimics leads to cardiomyocyte proliferation and promotes cardiac function post-MI through down-regulation of Hippo signaling in a mouse model. However, the therapy was met with several translational impediments, including off-target accumulation, a limited therapeutic time frame for effective treatment, and the inefficiency and costs associated with systemic delivery of miR302 mimics. The goal of this proposal is to develop an injectable hydrogel system to overcome these limitations by locally delivering miR302 to cardiac tissue after MI. Towards this, the first aim of this proposal is to develop guest-host assembled hydrogels based on cationic polyethyleneimine and neutral polyethylene glycol capable of (i) injection (flow through syringe or catheter), (ii) self-healing (for local deposition and retention at the injection site), and (iii) the encapsulation and release of active miR302 over tunable therapeutic windows. The second aim of this proposal is to apply this technology in a small animal model of MI to promote healing and improved global cardiac function. The long-term goal of this research is to develop a platform to deliver various forms of RNAi to cardiac tissue post-MI using a catheter-deliverable hydrogel engineered as an effective drug delivery system. In addition to the research proposal, this fellowship includes a training plan through which I will gain clinical experience, expand my scientific background through collaboration with the Atluri and Morrisey groups, and present my research findings both on and off campus.